Neonatal Alloimmune Thrombocytopenia:

Antenatal Management

Yoav Yinon, MDHead of Fetal Medicine UnitSheba Medical Center

Typical Case Scenario

32 yo, G2P1, 12 wk of gestation

OB Hx:

G1- Vaginal delivery @ 38wk, petechiae at birth,

PLT-30,000

How is NAIT diagnosed?

• Previous child with unexplained

thrombocytopenia

• Maternal-Paternal HPA incompatibility

• Maternal HPA antibodies against the

corresponding HPA antigen

NAIT-Diagnosis

Human platelet antigens

IUGR

IUFD

Miscarriages

HPA frequencies

Mom- HPA 1b/1b

Dad – HPA 1a/1aMom- HPA 1b/1b

Dad – HPA 1a/1b

The fetus is at risk Amniocentesis for fetal HPA typing

Fetal HPA-typing using free fetal DNA in maternal plasma

NAIT-Diagnosis

Scheffer et al., BJOG 2011

Neonatal Alloimmune

Thrombocytopenia

• Only around 10% of HPA-1a negative pregnant women produce HPA-antibodies despite carrying an HPA-1a positive fetus

• Association between maternal HLA and tendency to produce these antibodies

Neonatal Alloimmune

Thrombocytopenia

• Incidence- 1:1000-1:2000

(varies by ethnicity)

• Can occur in the first pregnancy

• Diagnosis is usually made following delivery of an affected child

Neonatal Alloimmune

Thrombocytopenia

• Rate of recurrence among subsequent infants is 90%

• Tends to worsen in subsequent pregnancies???

• The most feared complication: ICH

Neonatal Alloimmune

Thrombocytopenia

Killie et al., Haematologica 2008

What is the antenatal

management?

• Antenatal management is aimed at maintaining fetal platelet count on a safe level

• The optimal antenatal management has not been defined:

– Serial fetal platelet transfusions:

The half life of transfused platelets is very short

– IVIG± steroids

NAIT – Antenatal treatment

• Maternal: dilution of anti-HPA antibodies

• Placenta: blockage of the receptor (Fc-R)

• Fetus: blockage of the Fc-receptors on the

macrophages

No dose-effect studies have been done

IVIG- Mechanism

• Headache

• Fever

• Hemolytic anemia

• Laryngeal edema

• Renal failure

• Aseptic meningitis

• Thrombotic complications

IVIG- side effects

FBS-indicated therapy and empiric therapy have never been

prospectively compared in a randomized trial

-High risk of hemorrhagic complications from cordocentesis (5%)

-Risk for boosting the alloimmunization

Invasive: FBS in order to diagnose fetal

thrombocytopenia before therapy and to

evaluate subsequent fetal response

Non-invasive: Empiric IVIG for women with a

fetus at risk for NAIT

NAIT – Antenatal management

Fetal blood sampling at 20-22 weeks

If PLT<100,000 start IVIG

If PLT>100,00 FBS every 6-8 weeks

FBS after 4-6 wk to evaluate therapy

NAIT – Invasive approach

Lynch et al., Obstet Gynecol 1992

Fetal blood sampling

IUT-Complications

• 11 (6%) serious complications after

175 FBS:

– 9 emergent CS

– 1 IUFD 4 days post FBS

– 1 PPROM 4 days post FBS

• 19 (24%) delivered <34 wk

Berkowitz et al., Obstet Gynecol 2006

– Emergent CS d/t fetal

distress

– Half resulted in preterm

birth 34 weeks

– 14/54 (26%) resulted in

fetal/neonatal death

Winkelhorst et al., Blood 2017

Invasive treatment-complications

FBS/IUPT complications rate: 11% (54/497)

NAIT-Perinatal mortality

Mortality rate-4% (30/821)

17 (57%) d/t

FBS/IUPT

Winkelhorst et al., Blood 2017

7 (23%) d/t

ICH

6 (20%)

Undetermined

Rationale: - High recurrence rate of NAIT

- Desire to avoid risks of FBS

Advantages

-Highly effective

-Avoids risks of FBS

Disadvantages

-Overtreatment in some cases

-Inadequate therapy in other cases

Does these concerns outweigh the negative

side effects of repeated FBS?

NAIT – Non-invasive approach

To evaluate a non-invasive management of

NAIT, in which treatment included only blind

administration of immunoglobulin

Objective

17 women, 30 pregnancies at risk of NAIT

All fetuses antigen-positive

24 pregnancies:

IVIG treatment

6 pregnancies:

Refused treatment

•Weekly administration of IVIG 1 gr/kg without

monitoring platelet counts

•Started in 18-24 gestational week

and continued until delivery

Yinon et al., AJOG 2006

NAIT – Non-invasive approach

Yinon et al., AJOG 2006

PLT<50000

PLT at birth

ICH (n)DoseNumber of

fetuses

14%1691237Berkowitz (2007)

8%1180124Yinon (2006)

16%1360145Van den Akker (2007)

44%890127Bertrand (2011)

NAIT – Non-invasive approach

Kamphuis and Oepkes, Prenatal Diagnosis 2011

• 10-20% of fetuses do not seem to respond

• There is currently no explanation for this phenomenon

• The non-responders may be at risk for ICH although it seems extremely rare in IVIG treated fetuses

• IVIG may aid in protection against bleeding

NAIT – Non-invasive approach

• Non-invasive management of NAIT is highly effective and seems safe.

• The value of performing cordocentesis and platelet transfusion is doubtful in view of its risk for the fetus, and the effectiveness of IVIG therapy

NAIT – Non-invasive approach

• When to start treatment

• IVIG vs IVIG +steroids

• Different IVIG regimens:

0.5 g/kg, 1 g/kg, 2 g/kg

Non-invasive approach:

Unresolved issues

There are insufficient data to recommend a

specific gestational age or a specific dose

• Neurodevelopmental outcome of 50 children at a median age of 5, 37 were exposed to IVIG:

– Higher incidence of hearing disability in the group that did not receive IVIG

– Comparable IgG, IgA, IgM levels

– No difference in eczema or allergies between the 2 groups

IVIG treatment-Long term effect

Radder al, Early Hum Dev 2004

• For every 1000 women empiric therapy compared with FBS-indicated treatment:

– Decreased perinatal deaths from 31.7 to 11.8

– Increased number of infants with long-term neurologic deficits from 6.1 to 9.6

Cost effectiveness of empiric IVIG

Empiric IVIG therapy is a cost-effective strategy when the

rate of perinatal ICH is less than 28%

Thung and Grobman, AJOG 2005

Can the severity of thrombocytopenia

in NAIT be predicted?

PLT ≥ 50000PLT< 50000Maternal antibodyconcentration, IU/Ml

103< 28

213≥ 28

PPV- 86.7%, NPV-76.9%

NAIT – Prediction of severity

Sainio et al, Transfusion Medicine 2013

• Severe disease can occur even with low antibody titers

• Antibody titer can fluctuate over time

NAIT – Prediction of severity

Sainio et al, Transfusion Medicine 2013

History of previous ICH is the strongest predictor

PPV-90%, NPV-31%

• Antibody level- no consistent relationship

• HLA-DRB3*0101 genotype

• Glycosylation pattern of the Fc-part alloantibodies

• Endothelial function

NAIT – Prediction of severity

NAIT in recurrent pregnancies:

Does a good response to IVIG in one

pregnancy predict success in the

following one?

0

50000

100000

150000

200000

250000

300000

350000

400000

0 1 2 3 4

Pla

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t co

un

t-p

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lets

/μL

No. of treated pregnancy

H I J K L M

Batsry et al., ISUOG 2016

What is the antenatal

management in cases of

previous ICH?

Tiller et al., BMJ Open 2013

NAIT and Intracranial Haemorrhage

NOICH registry

592 pregnancies

43 cases of ICH

28 survivors9 dead after birth1 dead during labour5 dead in utero

39 HPA-1a

4 HPA-5a-5b

23 severe neuro disabilities 5 alive and well

NAIT and Intracranial Haemorrhage

• The majority of bleedings (54%) occurred before 28 wks

• The first born child was affected in most cases (63%)

• Median PLT count was 8000 (1000-27000)

• Antenatal treatment was given in 4/43 (9%) cases

Tiller et al., BMJ Open 2013

NAIT and Intracranial Haemorrhage

Tiller et al., BMJ Open 2013

In order to reduce the risk of recurrent ICHs in subsequent pregnancies, IVIG should be initiated before 20 weeks of gestation

37 pregnancies with previous ICH

NAIT and previous ICH

Bussel et al., AJOG 2010

Extremely high risk

Sibling ICH prior to 28 wks

(n=8)

Very high risk

Sibling ICH at 28-36 wks

(n=17)

High risk

Sibling ICH in perinatal period

(n=12)

Salvage treatment

5/8

Salvage treatment

13/17

Salvage treatment

7/12

ICH

1/8

ICH

2/17

ICH

2/12

Antenatal management of NAIT and

previous ICH (US)

Previous fetus

with ICH >28 wks

Previous fetus

with ICH < 28 wks

IVIG 1g/kg/wk at 12 wks

At 20 wks increase IVIG to 2g/kg/wk

or

Add prednisone 0.5 mg/kg/day

Pacheco et al., Obstet Gynecol 2011

At 28 wks IVIG 2g/kg/wk and

prednisone 0.5 mg/kg/day

IVIG 2g/kg/wk at 12 wks

At 20 wks add prednisone

1 mg/kg/day

Antenatal management of NAIT and

previous ICH (Europe)

Diagnosis of NAIT

Kamphuis and Oepkes, Prenatal Diagnosis 2011

IVIG 0.5 gr/kg/wk

Start at 28 wks

Sibling without ICH Sibling with ICH

IVIG 1 gr/kg/wk

Start at 16 wks

What should be the

mode of delivery?

• Elective CS

• Pre-delivery FBS in double set-up

Vaginal delivery if PLT>50,000

NAIT – Mode of delivery

No evidence that when PLT<50,000,

VD increases the risk for ICH

Our protocol (Sheba)

Diagnosis of NAIT

IVIG 1 gr/kg/wk

Start at 22 wks

Sibling without ICH Sibling with ICH

IVIG 1-2 gr/kg/wk

Start at 12 wks +

prednisone start at 20-28 wks

Elective CS or pre-delivery FBS at 37 wks

Ultrasound evaluation of the fetal brain every 4 weeks

History of previous newborn with

thrombocytopenia or ICH of

unknown etiology

Case Presentation

33 Y.O, G2P1, 25 wk

OB Hx:

G1 (2007): US @ 30 wk –

severe ICH.

PLT – ???

Autopsy- massive subdural

and subarachnoid

hemorrhage.

Work-up:

Mom: HPA-3b3b

Dad: HPA-3a3b

Fetus: HPA- 3a3b

Case Presentation

Should we treat with IVIG?

Should we do FBS?

No anti-HPA-3a antibodies were detected

Previous thrombocytopenia of

unknown etiology

Incompatibility at HPA lociNo maternal anti-HPA antibodies

Repeat maternal anti-HPA antibody testing and cross-

match with paternal platelets at 12, 24, 32 weeks

No further evaluation

Pacheco et al., Obstet Gynecol 2011

No incompatibility at HPA lociNo maternal anti-HPA antibodies

Test for maternal antibodies and cross-match with paternal

platelets at 30 weeks

Negative

No further evaluation

Negative

Should we screen for NAIT?

HPA 1 typing in 100,448 pregnant women

170 pregnancies were managed according

to the intervention program

Anti-HPA-1a was detected in 10.6% of these

2.1% were HPA 1a negative

55 had severe thrombocytopenia

3 had ICH

Screening for NAIT

• The prevalence of HPA-1a negative is 1-2%

• Only 10% of these patients will develop anti-HPA-1a

antibodies

• Of those, only 30% of neonates will have severe

thrombocytopenia

• 10-20% of them will develop ICH

Prevent 6 cases of ICH for 100,000 women screened

Is it possible to prevent HPA-1a

alloimmunization?

Prophylactic administration of PLT antibodies induces

antibody-mediated immune suppression and prevents poor

pregnancy outcome in a murine model of NAIT

Tiller et al., Transfusion 2012

Prevention of HPA-1a

alloimmunization

Tiller et al., Transfusion 2012

In cases in which there is antihuman platelet antigen

incompatibility and IVIG cannot be administered, PGD is a

reliable alternative to enable birth of unaffected children

Altarescu et al., Obstet Gynecol 2012

Summary

• Testing for NAIT should be done for any fetus or neonate

with an unexplained ICH or thrombocytopenia

• Preferred antenatal management:

Non-invasive approach of empiric IVIG therapy

• Management should be based on risk stratification:

More intensive treatment for patients with a history of ICH

• Pre-delivery FBS allows vaginal delivery in most patients

Research agenda

• Non-invasive method to predict severity of fetal

thrombocytopenia

• The role of screening of the HPA-status of

pregnant women

• Prevention of HPA-1a alloimmunization by HPA-1a

antibody therapy

Thanks for your attention